Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China; Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Third Military Medical University, Chongqing 400038, China.
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China; Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Third Military Medical University, Chongqing 400038, China.
Cancer Lett. 2015 Mar 1;358(1):76-84. doi: 10.1016/j.canlet.2014.12.040. Epub 2014 Dec 18.
Tumor cell stemness has been recognized as a key contributor to tumor initiation, progression and recurrence. Our previous studies have found that semaphorin-3F (SEMA3F), an axon guidance molecule in the development of central nervous system, inhibited the growth and metastasis of colorectal cancer (CRC). However, a possible role for SEMA3F in regulating cancer cell stemness remains unknown. Here, we report a novel mechanism of the acquirement of stemness of CRC cells regulated by SEMA3F. Knockdown of SEMA3F significantly promoted the self-renewal and tumorigenicity of CRC cells, and increased the expression of stemness-associated genes, while overexpressing SEMA3F reduced the stemness of CRC cells. Mechanistically, GTP-Rac1 was involved in SEMA3F mediated regulation of CRC cell stemness by targeting the Wnt/β-catenin pathway. Clinically, GTP-Rac1 expression was inversely correlated with SEMA3F levels in CRC samples and patients with SEMA3F(low)/GTP-Rac1(high) CRC showed poorer prognosis. Our findings demonstrate the ability of SEMA3F to inhibit the stemness of human CRC cells by suppressing Rac1 activation, which suggests a novel therapeutic approach for CRC.
肿瘤细胞干性被认为是肿瘤起始、进展和复发的关键因素。我们之前的研究发现，轴突导向分子 SEMA3F（神经递质 3F）抑制结直肠癌（CRC）的生长和转移。然而，SEMA3F 调节癌细胞干性的可能作用尚不清楚。在这里，我们报告了 SEMA3F 调控 CRC 细胞干性获得的新机制。SEMA3F 的敲低显著促进 CRC 细胞的自我更新和致瘤性，并增加了干性相关基因的表达，而过表达 SEMA3F 则降低了 CRC 细胞的干性。在机制上，GTP-Rac1 通过靶向 Wnt/β-catenin 通路参与 SEMA3F 介导的 CRC 细胞干性调节。临床上，CRC 样本中 GTP-Rac1 的表达与 SEMA3F 水平呈负相关，并且 SEMA3F(low)/GTP-Rac1(high) CRC 患者的预后较差。我们的研究结果表明，SEMA3F 通过抑制 Rac1 激活来抑制人 CRC 细胞的干性，这为 CRC 的治疗提供了一种新的方法。
